- Integrin αvβ6 (IC50 = 29.8 nM) [3]
- Integrin αvβ1 (IC50 = 19.2 nM) [3]

Inhibiting TGF - β activation: Bexotegrast (PLN - 74809) can inhibit the activation of TGF - β induced by integrins αvβ6 and αvβ1 in vitro. Through ligand - binding, cell adhesion, and TGF - β cell activation assays, it is found that the drug can reduce the expression of type I collagen gene by blocking the integrin - mediated TGF - β activation pathway, which is verified in precision - cut lung slices from idiopathic pulmonary fibrosis patients [3]

Anti - fibrotic effect: In bleomycin - challenged mice, Bexotegrast (PLN - 74809) can dose - dependently inhibit pulmonary Smad3 phosphorylation and collagen deposition, reducing the burden of pulmonary fibrosis. It shows a better anti - fibrotic effect than nintedanib or pirfenidone, and can more effectively reduce the collagen gene expression in the lung tissue of fibrotic mice [3]

Bleomycin - induced lung fibrosis mouse model: Induce lung fibrosis in mice with bleomycin. Divide the mice into different groups, and administer Bexotegrast (PLN - 74809) to the experimental groups at different doses, while the control group is given a placebo. After a certain period of treatment, sacrifice the mice, collect lung tissues, and detect the changes of pulmonary collagen deposition and Smad3 phosphorylation to evaluate the anti - fibrotic effect of the drug [3]

Pharmacokinetics [2]
The total and free exposures (maximum concentration and area under the concentration-time curve from 0 to 24 hours after administration) of bexoglucopyrans patients were predicted to increase in approximately proportionally with the dose (see Tables E3 and E4).

Safety and Tolerability at Week 12 [2] Overall, bexostat demonstrated good safety and tolerability during the 12-week treatment period (see Tables 2, 3, E1, and E2 in the online supplemental materials). Most treatment-emergent adverse events (TEAEs) that occurred during the treatment period were mild or moderate. The most common TEAEs are shown in Table 2. Diarrhea was the most common TEAE, occurring in 15 subjects (16.9%) in the bexostat (total) group and in 3 subjects (9.7%) in the placebo group. Among the subjects who reported diarrhea, 13 of the 15 subjects (86.7%) in the bexostat group were receiving background treatment with nintedanib, and 1 of the 3 subjects (33.3%) in the placebo group were receiving background treatment with nintedanib; 1 subject (6.7%) in the bexostat group was receiving pirfenidone (Table 3). Of the remaining patients with diarrhea who received bexoglucopyraxate monotherapy, one had a history of ulcerative colitis. Most diarrheal events (14 of 15; 93.3%) were mild to moderate; one patient receiving both bexoglucopyraxate and pirfenidone experienced grade 3 diarrhea. Four patients discontinued bexoglucopyraxate treatment due to complications from coronavirus disease (COVID-19) (n = 1), diarrhea (n = 2), and intestinal obstruction and acute kidney injury (n = 1). Two patients discontinued bexoglucopyraxate due to mild diarrhea (one was concurrently receiving nintedanib; the other was not receiving any basic treatment and had a history of ulcerative colitis). Dosage reduction of bexoglucopyraxate was not permitted according to the protocol. No serious adverse events related to the study drug were assessed. In the bexoglucopyraxate group, 2.3% of subjects reported treatment-emergent adverse events (TEAEs) for idiopathic pulmonary fibrosis/pulmonary fibrosis, compared to 9.7% in the placebo group. Only one case was an acute exacerbation of idiopathic pulmonary fibrosis (IPF). This subject had completed 12 weeks of 160 mg bexoglucopyride treatment and experienced the event 11 days after the last dose. The event was considered drug-independent and resolved the following day after hospitalization for corticosteroids and antibiotics. In the 320 mg bexoglucopyride group, a subject with stage III IPF, prior coronary artery disease, and chronic refractory atrial fibrillation experienced a serious and fatal acute respiratory failure adverse event following elective atrioventricular node ablation. The study drug did not cause significant changes in laboratory parameters, vital signs, physical examination results, or electrocardiogram results. Overall, bexoglucopyride was well tolerated when used in combination with IPF background therapy or as monotherapy (Tables 3, E1, and E2).

[1]. De novo design of highly selective miniprotein inhibitors of integrins αvβ6 and αvβ8. Nat Commun. 2023 Sep 13;14(1):5660.

[2]. Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Clinical Trial. Am J Respir Crit Care Med. 2024 Aug 15;210(4):424-434.

[3]. Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF. Respir Res. 2021 Oct 19;22(1):265.

αv integrins are key regulators of TGF-β activation and fibrosis in pulmonary fibrosis models. αvβ6 and αvβ1 are highly expressed in the lung tissue of patients with idiopathic pulmonary fibrosis, but are rarely expressed in normal tissues. Bessogaster (PLN-74809) is a small molecule oral drug that blocks TGF-β activation by inhibiting αvβ6 and αvβ1 and may slow or even stop the fibrosis process in patients with idiopathic pulmonary fibrosis. Currently, bessogaster is in phase II/III clinical trials for the treatment of idiopathic pulmonary fibrosis[3].

C27H38CL2N6O3

565.54

2775365-40-5

2376257-44-0

Typically exists as solids at room temperature

PLN-74809 hydrochloride; PLN-74809 HCl; PLN74809 hydrochloride; orb1739963; 2775365-40-5

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)